Wu Yuansheng, Zhu Yingjie, Chen Jie, Song Lili, Wang Chunping, Wu Yanglin, Chen Yanyang, Zheng Jiancheng, Zhai Yuankun, Zhou Xiang, Liu Youwen, Du Yawei, Cui Wenguo
Medical Center of Hip, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, 82 Qiming South Road, Luoyang, 471000, P. R. China.
Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China.
Adv Healthc Mater. 2025 Mar;14(7):e2403212. doi: 10.1002/adhm.202403212. Epub 2024 Nov 6.
Monocytes, as progenitors of macrophages and osteoclasts, play critical roles in various stages of bone repair, necessitating phase-specific regulatory mechanisms. Here, icariin (ICA) prodrug-like microspheres (ICA@GM) are developed, as lipid nanoparticle (LNP) transfection boosters, to construct mRNA-engineered monocytes for remodeling the bone microenvironment across multiple stages, including the acute inflammatory and repair phases. Initially, ICA@GM is prepared from ICA-conjugated gelatin methacryloyl via a microfluidics system. Then, monocyte-targeting IL-4 mRNA-LNPs are then prepared and integrated into injectable microspheres (mRNA-ICA@GM) via electrostatic and hydrogen bond interactions. After bone-defect injection, LNPs are controlled released from mRNA-ICA@GM within 3 days, rapidly transfecting monocytes for monocyte IL-4 mRNA-engineering, which effectively suppressed acute inflammatory responses via polarization programming and paracrine signaling. Afterwards, ICA is sustainably released as well via cleavable boronate esters across multiple stages, cooperatively boosting the mRNA-engineered monocytes to inhibit coenocytic fusion and osteoclastic function. Both in vitro and in vivo data indicated that mRNA-ICA@GM can not only reverse the inflammatory environment but also suppress monocyte-derived osteoclast formation to accelerate bone repair. In summary, mRNA-engineered monocytes and ICA prodrug-like microspheres are combined to achieve long-lasting multi-stage bone microenvironment regulation, offering a promising repair strategy.
单核细胞作为巨噬细胞和破骨细胞的祖细胞，在骨修复的各个阶段发挥着关键作用，这就需要阶段特异性的调节机制。在此，开发了类淫羊藿苷（ICA）前药微球（ICA@GM）作为脂质纳米颗粒（LNP）转染增强剂，构建经mRNA工程改造的单核细胞，以重塑包括急性炎症和修复阶段在内的多个阶段的骨微环境。首先，通过微流控系统由共轭明胶甲基丙烯酰基的ICA制备ICA@GM。然后，制备单核细胞靶向的IL-4 mRNA-LNP，并通过静电和氢键相互作用将其整合到可注射微球（mRNA-ICA@GM）中。骨缺损注射后，LNP在3天内从mRNA-ICA@GM中受控释放，迅速转染单核细胞进行单核细胞IL-4 mRNA工程改造，通过极化编程和旁分泌信号有效抑制急性炎症反应。之后，ICA也通过可裂解硼酸酯在多个阶段持续释放，协同增强经mRNA工程改造的单核细胞以抑制多核融合和破骨细胞功能。体外和体内数据均表明，mRNA-ICA@GM不仅可以逆转炎症环境，还可以抑制单核细胞衍生的破骨细胞形成，从而加速骨修复。总之，将经mRNA工程改造的单核细胞和类ICA前药微球相结合，可实现持久的多阶段骨微环境调节，提供了一种有前景的修复策略。
